rs114292876

chr11-103188554-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080463.2(DYNC2H1):c.7198A>G(p.Ile2400Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,868 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (8 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.48

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008184284).
• BP6: Variant 11-103188554-A-G is Benign according to our data. Variant chr11-103188554-A-G is described in ClinVar as [Benign]. Clinvar id is 220053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00579 (881/152192) while in subpopulation AFR AF= 0.0199 (829/41560). AF 95% confidence interval is 0.0188. There are 4 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.7198A>G	p.Ile2400Val	missense_variant	44/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.7198A>G	p.Ile2400Val	missense_variant	44/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.7198A>G	p.Ile2400Val	missense_variant	44/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.7198A>G	p.Ile2400Val	missense_variant	44/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+54135A>G		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*4743A>G		3_prime_UTR_variant, NMD_transcript_variant	42/51

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 878 AN: 152074 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00153 AC: 379 AN: 248478 Hom.: 5 AF XY: 0.00114 AC XY: 154 AN XY: 134826

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.000997

GnomAD4 exome AF: 0.000586 AC: 855 AN: 1458676 Hom.: 8 Cov.: 30 AF XY: 0.000497 AC XY: 361 AN XY: 725652

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.000940

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00579 AC: 881 AN: 152192 Hom.: 4 Cov.: 32 AF XY: 0.00566 AC XY: 421 AN XY: 74410

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.00690

ESP6500AA AF: 0.0215 AC: 78

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.00193 AC: 233

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Asphyxiating thoracic dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.068	T;T;.;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0082	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.48	N;.;.;N
REVEL	Benign	0.099
Sift	Benign	0.40	T;.;.;T
Sift4G	Benign	0.47	T;.;.;T
Polyphen		0.52	P;P;P;P
Vest4		0.54
MVP		0.60
MPC		0.074
ClinPred		0.030	T
GERP RS		5.8
Varity_R		0.12
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs114292876; hg19: chr11-103059283;